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Calcium Signaling

Martin D. Bootman

The Babraham Institute Babraham Research Campus, Cambridge CB22 3AT, United Kingdom Correspondence: [email protected]

Calcium ions regulate processes as diverse as cell motility, using London tap water (which contained calcium) sup- gene transcription, muscle contraction, and ported the contraction of isolated frog hearts, whereas sal- (Berridge et al. 2000). The first realization that they are crit- ine made up using distilled water (which lacked calcium) ical for cellular function is often attributed to Sydney Ring- could not. Subsequent work revealed that numerous cell er, who discovered in 1883 that saline solution made up biological processes are controlled by calcium (Carafoli

Hormones Neurotransmitters EGFR GPCR Orai1 SRC βγ β γ G Gα PLC PIP2 PLC STIM GTP

IP3 Ca2+ PKC DAG

IP3R

RyR ER store

Ca2+

cADPR

CaM Calcineurin (PP2B) Effects Other effects

NFAT

Cytoplasm

Nucleus NFAT

Figure 1. (simplified view).

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Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011171 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a011171 1 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press M.D. Bootman

2+ Cyclic- Voltage- or Ca TCR gated channel 2+ + 2+ nucleotide- AChR GPCR EGFR Ca Na /Ca gated channel Orai1 PMCA exchanger SRC PLCβ Gβγ Gα γ PIP2 PLC STIM GTP

MAPK pathway 2+ IP3 Ca Na+ cGMP Ca2+ cAMP PKC DAG IP3R TRPV1 or TRPM8 2+ Na+ Ca ER/SR store Mitochondrion TRPP2 Na+/Ca2+ 2+ Ca2+ Ca exchanger Ca2+ RyR TPC Ca2+

NAADP SERCA Ca2+ uniporter cADPR Golgi Ca2+ Ca2+ TRPMLs Calcineurin CaM TRPM2 (PP2B) IP3R TPC Synaptotagmin Other CamKII effects Ca2+ NFAT Secretion Neurite growth MAPK pathway Other effects Muscle SPCA Ca2+ contraction

Cytoplasm

Nucleus CamKIV NFAT

CBP CREB

Figure 2. Calcium signaling.

2003). Particularly important was the discovery in the phosphatases, transcription factors such as NF-AT, and the 1950s that calcium triggers skeletal muscle contraction by ubiquitous calcium-binding (CaM). binding to troponin C and that calcium can be sequestered Electrical, hormonal, and mechanical stimulation of in the sarcoplasmic reticulum. These studies led to the no- cells can produce calcium signals by causing entry of the tion that calcium signals inside cells oscillate: the cytoplas- ion across the plasma membrane or its release from intra- mic calcium concentration increases, a particular effector cellular stores. Binding of to G-protein-coupled is activated, and then the calcium signal is reversed to reset receptors (GPCRs), for example, leads to generation of the the system (see Figs. 1 and 2). Cells use a “toolkit” of chan- second messenger inositol 1,4,5-trisphosphate (IP3), which nels, pumps, and cytosolic buffers to control calcium levels releases calcium from intracellular stores such as the endo- (Berridge et al. 2000). Numerous are modulated di- plasmic reticulum. By contrast, electrical or neurotrans- rectly or indirectly by calcium. These include and mitter stimulation of neurons causes calcium to enter

2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a011171 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Calcium Signaling cells from outside via channels in the plasma membrane. neurin (Berridge 2006). Alternatively, it can act via the This can increase the average cytosolic calcium concentra- ubiquitous calcium-binding protein CaM. The interaction tion from around 100 nM to around 1 mM. Close to an ac- of calcium with CaM leads to a rearrangement of the pro- tive channel the calcium concentration can reach tens of tein that allows it to bind and allosterically regulate target micromolar. Such local hot-spots of calcium are used by molecules such as the calcium/calmodulin-dependent kin- cells to activate specific process that are generally not sensi- ases CaMKII and CaMKIV.CaM is mobile within cells and tive to the bulk cytosolic calcium concentration (Bootman can associate with its targets after binding calcium. How- et al. 2001). ever, in some cases, it is prebound to its target, which pro- Cellular calcium signaling proteomes are tissue-specif- vides rapid control. Ultimately, calcium signals are reversed ic, producing unique calcium signals that suit a tissue’s by the action of pumps such as the sarco/endoplasmic re- physiology (Berridge et al. 2003). For example, cardiac my- ticulum ATPases (SERCA) that return it from the cytosol to ocytes require a rapid (hundreds of milliseconds) whole- intracellular stores or the external milieu. cell calcium transient to trigger contraction every second (Bers 2002), whereas cells that are not electrically excitable REFERENCES typically display calcium oscillations that last for tens of seconds, and can have a periodicity of several minutes, to Berridge MJ. 2006. Calcium microdomains: Organization and function. control gene expression and metabolism (Dupont et al. Cell Calcium 40: 405–412. Berridge MJ, Lipp P,Bootman MD. 2000. The versatility and universality 2011). The rapid calcium signals within myocytes are of calcium signalling. Nat Rev Mol Cell Biol 1: 11–21. caused by calcium entering through voltage-activated calci- Berridge MJ, Bootman MD, Roderick HL. 2003. Calcium signalling: um channels in the plasma membrane, which then triggers Dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4: calcium release via ryanodine receptors on the sarcoplas- 517–529. Bers DM. 2002. Cardiac excitation-contraction coupling. Nature 415: mic reticulum. The slower calcium signals in nonexcitable 198–205. cells typically rely on IP3, which binds to channels (InsP3- Bootman MD, Lipp P,Berridge MJ. 2001. The organisation and functions + Rs) on the , or potentially nicotinic of local Ca2 signals. J Cell Sci 114: 2213–2222. acid adenine dinucleotide phosphate-gated calcium chan- Carafoli E. 2003. The calcium-signalling saga: Tapwater and protein crys- tals. Nat Rev Mol Cell Biol 4: 326–332. nels (two pore channels) on acidic organelles, leading to Dupont G, Combettes L, Bird GS, Putney JW.2011. Calcium oscillations. release of calcium into the cytoplasm (Galione 2011). Cal- Cold Spring Harb Perspect Biol 3: a004226. cium signals can also pass through gap junctions to coordi- Galione A. 2011. NAADP receptors, Cold Spring Harb Perspect Biol 3: nate activities of neighboring cells (Sanderson et al. 1994). a004036. Sanderson MJ, Charles AC, Boitano S, Dirksen ER. 1994. Mechanisms The actions of calcium can be mediated by direct bind- and function of intercellular calcium signaling. Mol Cell Endocrinol ing of calcium to effectors, such as the phosphatase calci- 98: 173–187.

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Calcium Signaling

Martin D. Bootman

Cold Spring Harb Perspect Biol 2012; doi: 10.1101/cshperspect.a011171

Subject Collection Signal Transduction

Cell Signaling and Stress Responses Second Messengers Gökhan S. Hotamisligil and Roger J. Davis Alexandra C. Newton, Martin D. Bootman and John D. Scott Protein Regulation in Signal Transduction Signals and Receptors Michael J. Lee and Michael B. Yaffe Carl-Henrik Heldin, Benson Lu, Ron Evans, et al. Synaptic Signaling in Learning and Memory Cell Death Signaling Mary B. Kennedy Douglas R. Green and Fabien Llambi Vertebrate Reproduction Signaling Networks that Regulate Cell Migration Sally Kornbluth and Rafael Fissore Peter Devreotes and Alan Rick Horwitz Signaling in Lymphocyte Activation Signaling Networks: Information Flow, Doreen Cantrell Computation, and Decision Making Evren U. Azeloglu and Ravi Iyengar Signaling in Muscle Contraction Signal Transduction: From the Atomic Age to the Ivana Y. Kuo and Barbara E. Ehrlich Post-Genomic Era Jeremy Thorner, Tony Hunter, Lewis C. Cantley, et al. Toll-Like Receptor Signaling Signaling by the TGFβ Superfamily Kian-Huat Lim and Louis M. Staudt Jeffrey L. Wrana Signaling Pathways that Regulate Cell Division Subversion of by Pathogens Nicholas Rhind and Paul Russell Neal M. Alto and Kim Orth

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